Crystalline bromodomain inhibitors

ABSTRACT

N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide and crystalline forms thereof are suitable pharmaceutical ingredients for pharmaceutical compositions useful in the treatment of disease, for example, cancer.

CROSS-REFERENCE PATENT

This patent application claims priority to U.S. Provisional PatentApplication No. 61/840,777 filed Jun. 28, 2013. The entire text of thisapplication is incorporated by reference into this patent application.

BACKGROUND OF THE INVENTION

Bromodomains refer to conserved protein structural folds which bind toN-acetylated lysine residues that are found in some proteins. The BETfamily of bromodomain containing proteins is comprised of four members(BRD2, BRD3, BRD4 and BRDt). Each member of the BET family employs twobromodomains to recognize N-acetylated lysine residues found primarily,but not exclusively, on the amino-terminal tails of histone proteins.These interactions modulate gene expression by recruiting transcriptionfactors to specific genome locations within chromatin. For example,histone-bound BRD4 recruits the transcription factor P-TEFb topromoters, resulting in the expression of a subset of genes involved incell cycle progression (Yang et al., Mol. Cell. Biol. 28: 967-976(2008)). BRD2 and BRD3 also function as transcriptional regulators ofgrowth promoting genes (LeRoy et al., Mol. Cell. 30: 51-60 (2008)). BETfamily members were recently established as being important for themaintenance of several cancer types (Zuber et al., Nature 478: 524-528(2011); Mertz et al; Proc. Nat'l. Acad. Sci. 108: 16669-16674 (2011);Delmore et al., Cell 146: 1-14, (2011); Dawson et al., Nature 478:529-533 (2011)). BET family members have also been implicated inmediating acute inflammatory responses through the canonical NF-KBpathway (Huang et al., Mol. Cell. Biol. 29: 1375-1387 (2009)) resultingin the upregulation of genes associated with the production of cytokines(Nicodeme et al., Nature 468: 1119-1123, (2010)). Suppression ofcytokine induction by BET bromodomain inhibitors has been shown to be aneffective approach to treat inflammation-mediated kidney disease in ananimal model (Zhang, et al., J. Biol. Chem. 287: 28840-28851 (2012)).BRD2 function has been linked to predisposition for dyslipidemia orimproper regulation of adipogenesis, elevated inflammatory profiles andincreased susceptibility to autoimmune diseases (Denis, DiscoveryMedicine 10: 489-499 (2010)). The human immunodeficiency virus utilizesBRD4 to initiate transcription of viral RNA from stably integrated viralDNA (Jang et al., Mol. Cell, 19: 523-534 (2005)). Treatment of db/dbmice with a BET specific bromodomain inhibitor has been shown toattenuate proteinuria, thus providing a potential new treatment fordiabetic nephropathy (Liu, et al., “Role of Transcription FactorAcetylation in Diabetic Kidney Disease” Diabetes, DOI: 10.2337/db13-1810(2014)). BET bromodomain inhibitors have also been shown to reactivateHIV transcription in models of latent T cell infection and latentmonocyte infection (Banerjee, et al, J. Leukocyte Biol. 92(6): 1147-1154(2012)). BRDt has an important role in spermatogenesis that is blockedby BET bromodomain inhibitors (Matzuk, et al., Cell 150: 673-684(2012)). Studies with BET inhibitors have demonstrated proof-of-conceptefficacy in animal models of sepsis and endotoxic shock (Nicodeme, etal., Nature 468: 1119-1123 (2010)), insulin resistance and hepaticsteatosis (Bradner, et al., Composition and methods for modulatingmetabolism. WO2011/143651A1), idiopathic pulmonary fibrosis (Tang, etl., Am. J. Pathol. 183: 470-479 (2013)) and heart failure (Spiltoir, etal., J. Mol. Cellular. Cardiol. 63: 175-179 (2013), Anand, et al., Cell154: 569-582 (2013)). Accordingly, there is an ongoing medical need todevelop new drugs and crystalline forms thereof to treat theseindications.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a powder X-ray diffraction (PXRD) scan ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideForm I.

FIG. 2 provides a differential scanning calorimeter (DSC) thermogram ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideForm I.

FIG. 3 provides a TGA curve ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideForm I.

FIG. 4 provides a powder X-ray diffraction (PXRD) scan ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideForm II.

FIG. 5 provides a differential scanning calorimeter (DSC) thermogram ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideForm II.

FIG. 6 provides a TGA curve ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideForm II.

SUMMARY

In one aspect the present invention relates to an isolated crystallineform ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,wherein the crystalline form has a powder X-ray diffraction patterncomprising three or more 2θ peak values ±0.2 selected from the groupconsisting of: 6.2°, 9.0°, 12.3°, 12.6°, 15.6°, 22.1°, 25.6°, 26.3°,27.0°, and 27.3°. In one aspect the present invention relates to anisolated crystalline form ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,wherein the crystalline form has a powder X-ray diffraction patterncomprising the following 2θ peak values ±0.2: 6.2°, 9.0°, 12.3°, 12.6°,15.6°, 22.1°, 25.6°, 26.3°, 27.0°, and 27.3°. In certain embodiments,the powder X-ray diffraction pattern comprises the following 2θ peakvalues ±0.2: 6.2°, 9.0°, 11.0°, 12.3°, 12.6°, 13.1°, 14.1°, 15.6°,16.4°, 16.5°, 16.9°, 17.8°, 18.1°, 18.3°, 18.9°, 20.4°, 21.1°, 21.6°,21.8°, 22.1°, 22.9°, 23.2°, 24.4°, 24.7°, 25.6°, 26.3°, 27.0°, and27.3°. In certain embodiments, the powder X-ray diffraction patterncomprises three, four, five, or six 20 peak values ±0.2 selected fromthe group consisting of 6.2°, 9.0°, 12.3°, 12.6, 15.6°, 22.1°, 25.6°,26.3°, 27.0°, and 27.3°. In certain embodiments, the powder X-raydiffraction pattern comprises six 2θ peak values ±0.2 selected from thegroup consisting of 6.2°, 9.0°, 12.3°, 12.6, 15.6°, 22.1°, 25.6°, 26.3°,27.0°, and 27.3°. In certain embodiments, the powder X-ray diffractionpattern comprises five 2θ peak values ±0.2 selected from the groupconsisting of 6.2°, 9.0°, 12.3°, 12.6, 15.6°, 22.1°, 25.6°, 26.3°,27.0°, and 27.3°. In certain embodiments, the powder X-ray diffractionpattern comprises four 2θ peak values ±0.2 selected from the groupconsisting of 6.2°, 9.0°, 12.3°, 12.6, 15.6°, 22.1°, 25.6°, 26.3°,27.0°, and 27.3°. In certain embodiments, the powder X-ray diffractionpattern comprises three 2θ peak values ±0.2 selected from the groupconsisting of 6.2°, 9.0°, 12.3°, 12.6, 15.6°, 22.1°, 25.6°, 26.3°,27.0°, and 27.3°. In certain embodiments, the powder X-ray diffractionpattern comprises the following 20 peak values ±0.2: 6.2°, 9.0°, 12.3°,12.6, 15.6°, 22.1°, 25.6°, 26.3°, 27.0°, and 27.3°. In certainembodiments, the powder X-ray diffraction pattern comprises thefollowing 20 peak values ±0.2: 6.2°, 9.0°, 12.3°, 12.6°, and 15.6°. Incertain embodiments, the powder X-ray diffraction pattern comprises thefollowing 2θ peak values ±0.2: 22.1°, 25.6°, 26.3°, 27.0°, and 27.3°. Incertain embodiments, the powder X-ray diffraction pattern comprises peakvalues ±0.2 at 2θ positions 6.2°, 9.0°, 12.3°, 12.6°, 13.1°, 14.1°,16.4°, 16.5°, 16.9°, 17.8°, 18.1°, 18.3°, and 18.9°. In certainembodiments, the powder X-ray diffraction pattern comprises peak values±0.2 at 2θ positions 6.2°, 9.0°, 12.3°, 12.6°, 13.1°, 14.1°, 18.1°, and18.9°. In certain embodiments, the powder X-ray diffraction patterncomprises peak values ±0.2 at 2θ positions 6.2°, 9.0°, 12.3°, 12.6°,13.1°, and 18.1°. In certain embodiments, the powder X-ray diffractionpattern comprises peak values ±0.2 at 2θ positions 9.0°, 12.3°, 12.6°,13.1°, and 18.1°. In certain embodiments, crystalline form II has adifferential scanning calorimetry thermogram endotherm between 240 and242° C. In certain embodiments, crystalline form II has a differentialscanning calorimetry thermogram endotherm at approximately 241° C. Incertain embodiments, the endotherm is determined using DSC at a heatingrate of 10° C./min. In certain embodiments, the powder X-ray diffractionpattern comprises peak values ±0.2 at 2θ positions 6.2°, 9.0°, 11.0°,12.2°, 12.6°, 13.1°, 14.1°, 15.5°, 16.3°, 16.5°, 16.9°, 17.8°, 18.0°,18.3°, 18.9°, 20.4°, 21.0°, 21.6°, 21.8°, 22.1°, 22.9°, 23.2°, 24.4°,24.6°, 25.5°, 26.3°, 26.9°, and 27.2. In certain embodiments, the powderX-ray diffraction pattern comprises peak values ±0.2 at 2θ positions±0.2 selected from the group consisting of: 6.2°, 9.0°, 12.2°, 12.6°,15.5°, 22.1°, 25.5°, 26.3°, 26.9°, and 27.2°.

In another aspect the present invention relates to pharmaceuticalcompositions comprising crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,and at least one pharmaceutically acceptable carrier. In certainembodiments, the pharmaceutical composition is a solid dosage form.

In another aspect the present invention relates to methods for treatingcancer in a subject comprising administering a therapeutically effectiveamount of a pharmaceutical composition comprising crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideand at least one pharmaceutically acceptable carrier, to a subject inneed thereof. In certain embodiments, the cancer is selected from thegroup consisting of: acoustic neuroma, acute leukemia, acute lymphocyticleukemia, acute myelocytic leukemia (monocytic, myeloblastic,adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic andpromyelocytic), acute t-cell leukemia, basal cell carcinoma, bile ductcarcinoma, bladder cancer, brain cancer, breast cancer, bronchogeniccarcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma,chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic(granulocytic) leukemia, chronic myelogenous leukemia, colon cancer,colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse largeB-cell lymphoma, dysproliferative changes (dysplasias and metaplasias),embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma,epithelial carcinoma, erythroleukemia, esophageal cancer,estrogen-receptor positive breast cancer, essential thrombocythemia,Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicularcancer, glioma, glioblastoma, gliosarcoma, heavy chain disease,hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitiveprostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer,lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia,lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies ofT-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midlinecarcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small cell lung carcinoma, solid tumors (carcinomas andsarcomas), small cell lung cancer, stomach cancer, squamous cellcarcinoma, synovioma, sweat gland carcinoma, thyroid cancer,Waldenström's macroglobulinemia, testicular tumors, uterine cancer andWilms' tumor. In certain embodiments, the method further comprisesadministering a therapeutically effective amount of at least oneadditional therapeutic agent. In certain embodiments, the additionaltherapeutic agent is selected from the group consisting of cytarabine,bortezomib, and 5-azacitidine.

In another aspect, the present invention relates to a method of treatinga disease or condition in a subject comprising administering atherapeutically effective amount of a crystalline Form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideto a subject in need thereof, wherein said disease or condition isselected from the group consisting of: Addison's disease, acute gout,ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease,bullous skin diseases, cardiac myopathy, cardiac hypertrophy, chronicobstructive pulmonary disease (COPD), Crohn's disease, dermatitis,eczema, giant cell arteritis, glomerulonephritis, heart failure,hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease,lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis,organ transplant rejection, osteoarthritis, pancreatitis, pericarditis,Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis,psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosingcholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis,toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis,vitiligo, vasculitis, and Wegener's granulomatosis. In certainembodiments, the method further comprises administering atherapeutically effective amount of at least one additional therapeuticagent.

In another aspect, the present invention relates to a method of treatinga chronic kidney disease or condition in a subject comprisingadministering a therapeutically effective amount of a crystalline FormII ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideto a subject in need thereof, wherein said disease or condition isselected from the group consisting of: diabetic nephropathy,hypertensive nephropathy, HIV-associated nephropathy,glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmentalglomerulosclerosis, membranous glomerulonephritis, minimal changedisease, polycystic kidney disease and tubular interstitial nephritis.In certain embodiments, the method further comprises administering atherapeutically effective amount of at least one additional therapeuticagent.

In another aspect, the present invention relates to a method of treatingan acute kidney injury or disease or condition in a subject comprisingadministering a therapeutically effective amount of a crystalline FormII ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideto a subject in need thereof, wherein said acute kidney injury ordisease or condition is selected from the group consisting of:ischemia-reperfusion induced kidney disease, cardiac and major surgeryinduced kidney disease, percutaneous coronary intervention inducedkidney disease, radio-contrast agent induced kidney disease, sepsisinduced kidney disease, pneumonia induced kidney disease, and drugtoxicity induced kidney disease. In certain embodiments, the methodfurther comprises administering a therapeutically effective amount of atleast one additional therapeutic agent.

In another aspect, the present invention relates to methods of treatingAIDS in a subject comprising administering a therapeutically effectiveamount of a crystalline Form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideto a subject in need thereof. In certain embodiments, the method furthercomprises administering a therapeutically effective amount of at leastone additional therapeutic agent.

In another aspect, the present invention relates to a method of treatingobesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease,metabolic syndrome, hepatic steatosis, type II diabetes, insulinresistance, diabetic retinopathy or diabetic neuropathy in a subjectcomprising administering a therapeutically effective amount of acrystalline Form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideto a subject in need thereof. In certain embodiments, the method furthercomprises administering a therapeutically effective amount of at leastone additional therapeutic agent.

In another aspect, the present invention relates to a methods ofcontraception in a male subject comprising administering atherapeutically effective amount of a crystalline Form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideto a subject in need thereof. In certain embodiments, the method furthercomprises administering a therapeutically effective amount of at leastone additional therapeutic agent.

A further aspect of the invention provides the use of a crystalline FormII ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,alone or in combination with at least one additional therapeutic agent,in the manufacture of a medicament for treating or preventing conditionsand disorders disclosed herein, with or without a pharmaceuticallyacceptable carrier.

In certain embodiments, the invention provides the use of a crystallineForm II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,alone or in combination with at least one additional therapeutic agent,in the manufacture of a medicament for treating cancer, with or withouta pharmaceutically acceptable carrier.

As mentioned above, crystalline Form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidemay provide advantages in formulating pharmaceutical compositions.Accordingly, one aspect of the present invention relates to apharmaceutical composition comprising theN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidein crystalline form, and a pharmaceutically acceptable carrier. In afurther embodiment, the composition according to the present inventioncomprisesN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideForm II as described above, alone or in combination with a secondtherapeutic agent, and a pharmaceutically acceptable carrier.

Another aspect relates to a process for preparing crystalline Form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide.

In another aspect the present invention relates to methods of making apharmaceutical composition comprisingN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideand a pharmaceutically acceptable carrier, comprising: mixing anisolated crystalline form ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,wherein the crystalline form has a powder X-ray diffraction patterncomprising three or more 2θ peak values ±0.2 selected from the groupconsisting of: 6.2°, 9.0°, 12.3°, 12.6°, 15.6°, 22.1°, 25.6°, 26.3°,27.0°, and 27.3°, with a pharmaceutically acceptable carrier.

In another aspect the present invention relates to compositionscomprising greater than 90% (w/w) crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,wherein the crystalline form has a powder X-ray diffraction patterncomprising three or more 2θ peak values ±0.2 selected from the groupconsisting of: 6.2°, 9.0°, 12.3°, 12.6°, 15.6°, 22.1°, 25.6°, 26.3°,27.0°, and 27.3°. In certain embodiments, the composition comprisesbetween 90-99% (w/w) crystalline form II.

DETAILED DESCRIPTION

N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidecan be prepared as a crystalline form which is termed crystalline FormII. As used herein, a crystalline form of a compound refers to the samechemical entity, but in a different crystalline arrangement.N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideis an inhibitor of human BRD4, and of the proliferation of the breastcancer cell line MX-1.

It is noted that, as used in this specification and the intended claims,the singular form “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a compound” includes a single compound as well as one or more of thesame or different compounds, reference to “a pharmaceutically acceptablecarrier” refers to a single pharmaceutically acceptable carrier as wellas one or more pharmaceutically acceptable carriers, and the like.

When used in reference to crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,which is greater than about 90% pure. This means that theN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidecrystal form II does not contain more than about 10% of any othercompound and, in particular, does not contain more than about 10% ofcrystal form I. More preferably, the term “substantially pure” refers tocrystalline Form II, which is greater than about 95% pure. This meansthat crystalline Form II does not contain more than about 5% of anyother compound and, in particular, does not contain more than about 5%of crystalline Form I. Even more preferably, the term “substantiallypure” refers to crystalline Form II, which is greater than about 97%pure. This means that crystalline Form II does not contain more thanabout 3% of any other compound, and, in particular, does not containmore than about 3% of crystalline Form I.

The crystalline Form I ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidemay also be referred to as “Form I ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,”or by similar expressions, and is having the physiochemical parametersoutlined herein. The crystalline Form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidemay also be referred to as “Form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,”or by similar terms, and is having the physiochemical parametersoutlined herein.

In certain aspects, the present invention further relates to apharmaceutical composition comprisingN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideForm II and a pharmaceutically acceptable carrier.

The crystalline forms ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,for example Form II, can be useful as an active pharmaceuticalingredient (API) in the preparation of pharmaceutical compositionssuitable for any route of administration, including oral, to a subjectin need thereof. Other routes of administration include, withoutlimitation, parenteral, sublingual, buccal, intranasal, pulmonary,topical, transdermal, intradermal, ocular, otic, rectal, vaginal,intragastric, intracranial, intrasynovial and intra-articular routes.

N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideis present in a pharmaceutical composition of the invention in an amountthat can be therapeutically effective when the composition isadministered to a subject in need thereof according to an appropriateregimen. Typically, a unit dose (the amount administered at a singletime), which can be administered at an appropriate frequency, e.g.,twice daily to once weekly, is about 10 to about 1,000 mg, depending onthe compound in question. Where frequency of administration is oncedaily (q.d.), unit dose and daily dose are the same. Illustratively, theunit dose is typically about 25 to about 1,000 mg, more typically about50 to about 500 mg, for example about 50, about 100, about 150, about200, about 250, about 300, about 350, about 400, about 450 or about 500mg.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type.Pharmaceutically acceptable carriers include but are not limited to, forexample, encapsulating materials and additives such as absorptionaccelerators, antioxidants, binders, buffers, carriers, coating agents,coloring agents, diluents, disintegrating agents, emulsifiers,extenders, fillers, flavoring agents, glidants, humectants, lubricants,perfumes, preservatives, propellants, releasing agents, sterilizingagents, sweeteners, solubilizers, wetting agents, mixtures thereof andthe like.

Pharmaceutically acceptable carriers for the preparation of formulationscomprising or made with crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideto be administered orally in solid dosage form include, for example,agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate,1,3-butylene glycol, carbomers, castor oil, cellulose, celluloseacetate, cocoa butter, copovidone, corn starch, corn oil, cottonseedoil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyllaureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose,glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol,isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt,mannitol, monoglycerides, olive oil, povidone, peanut oil, potassiumphosphate salts, potato starch, povidone, propylene glycol, Ringer'ssolution, safflower oil, sesame oil, silicon dioxide, sodiumcarboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate,sodium sorbitol, sodium stearylfumarate, soybean oil, stearic acids,stearyl fumarate, sucrose, surfactants, talc, tragacanth,tetrahydrofurfuryl alcohol, triglycerides, vitamin E and derivativesthereof, water, mixtures thereof and the like.

Pharmaceutically acceptable carriers for the preparation of formulationscomprising or made with crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideto be administered ophthalmically or orally in liquid dosage formsinclude, for example, 1,3-butylene glycol, castor oil, corn oil,cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil,groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols,propylene glycol, sesame oil, water, mixtures thereof and the like.

Pharmaceutically acceptable carriers for the preparation of formulationscomprising or made with crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideto be administered osmotically include, for example,chlorofluorohydrocarbons, ethanol, water, mixtures thereof and the like.

Pharmaceutically acceptable carriers for the preparation of formulationscomprising or made with crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideto be administered parenterally include, for example, 1,3-butanediol,castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil,liposomes, oleic acid, olive oil, peanut oil, Ringer's solution,safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodiumchloride solution, water, mixtures thereof and the like.

Pharmaceutically acceptable carriers for the preparation of formulationscomprising or made with crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideto be administered rectally or vaginally include, but are not limitedto, cocoa butter, polyethylene glycol, wax, mixtures thereof and thelike.

The composition is normally administered in an amount providing atherapeutically effective daily dose of the drug. The term “daily dose”herein means the amount of drug administered per day, regardless of thefrequency of administration. For example, if the subject receives a unitdose of 150 mg twice daily, the daily dose is 300 mg. Use of the term“daily dose” will be understood not to imply that the specified dosageamount is necessarily administered once daily. However, in a particularembodiment the dosing frequency is once daily (q.d.), and the daily doseand unit dose in this embodiment are the same.

What constitutes a therapeutically effective dose depends on theparticular compound, the subject (including species and body weight ofthe subject), the disease (e.g., the particular type of cancer) to betreated, the stage and/or severity of the disease, the individualsubject's tolerance of the compound, whether the compound isadministered in monotherapy or in combination with one or more otherdrugs, e.g., other chemotherapeutics for treatment of cancer, and otherfactors. Thus the daily dose can vary within wide margins, for examplefrom about 10 to about 1,000 mg. Greater or lesser daily doses may beappropriate in specific situations. It will be understood thatrecitation herein of a “therapeutically effective” dose herein does notnecessarily require that the drug be therapeutically effective if only asingle such dose is administered; typically therapeutic efficacy dependson the composition being administered repeatedly according to a regimeninvolving appropriate frequency and duration of administration. Asuitable therapeutically effective dose can be selected by the physicianof ordinary skill without undue experimentation. The physician may, forexample, start a cancer patient on a course of therapy with a relativelylow daily dose and titrate the dose upwards over a period of days orweeks, to reduce risk of adverse side-effects.

Illustratively, suitable doses ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideare generally about 10 to about 1,000 mg/day, more typically about 50 toabout 500 mg/day or about 200 to about 400 mg/day, for example about 50,about 100, about 150, about 200, about 250, about 300, about 350, about400, about 450 or about 500 mg/day, administered at an average dosageinterval of 3 to 10 days, or about 4 to 8 days, or about 7 days.

A composition comprising crystallineN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideForm II suitable for use in monotherapy or in combination therapy, forexample with other chemotherapeutics or with ionizing radiation.

Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,and pharmaceutical compositions comprising crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,can be administered to a subject suffering from a bromodomain-mediateddisorder or condition. The term “administering” refers to the method ofcontacting a compound with a subject. Thus, the crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidecan be administered by injection, that is, intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally,parentally, or intraperitoneally. It can also be administered byinhalation, for example, intranasally. Additionally, crystalline form IIofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidecan be administered transdermally, topically, via implantation,transdermally, topically, and via implantation. In certain embodiments,crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidemay be delivered orally. In other embodiments, crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidecan also be delivered rectally, bucally, intravaginally, ocularly, or byinsufflation. Bromodomain-mediated disorders and conditions can betreated prophylactically, acutely, and chronically using a crystallineform II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,depending on the nature of the disorder or condition.

A “bromodomain-mediated disorder or condition” is characterized by theparticipation of one or more bromodomains (e.g., BRD4) in the inception,manifestation of one or more symptoms or disease markers, severity, orprogression of a disorder or condition.

Accordingly, crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidemay be used to treat cancer, including, but not limited to acousticneuroma, acute leukemia, acute lymphocytic leukemia, acute myelocyticleukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma,astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia,basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer,breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma,chordoma, choriocarcinoma, chronic leukemia, chronic lymphocyticleukemia, chronic myelocytic (granulocytic) leukemia, chronicmyelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma,glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma,hepatoma, hepatocellular cancer, hormone insensitive prostate cancer,leiomyosarcoma, leukemia, liposarcoma, lung cancer,lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia,lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies ofT-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midlinecarcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small cell lung carcinoma, solid tumors (carcinomas andsarcomas), small cell lung cancer, stomach cancer, squamous cellcarcinoma, synovioma, sweat gland carcinoma, thyroid cancer,Waldenström's macroglobulinemia, testicular tumors, uterine cancer andWilms' tumor.

Further, crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidemay be used to treat inflammatory diseases, inflammatory conditions, andautoimmune diseases, including, but not limited to: Addison's disease,acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet'sdisease, bullous skin diseases, cardiac myopathy, cardiac hypertrophy,chronic obstructive pulmonary disease (COPD), Crohn's disease,dermatitis, eczema, giant cell arteritis, glomerulonephritis, heartfailure, hepatitis, hypophysitis, inflammatory bowel disease, Kawasakidisease, lupus nephritis, multiple sclerosis, myocarditis, myositis,nephritis, organ transplant rejection, osteoarthritis, pancreatitis,pericarditis, Polyarteritis nodosa, pneumonitis, primary biliarycirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis,scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus,Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes,ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener'sgranulomatosis.

Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,may be used to treat AIDS.

Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,may be used to treat chronic kidney disease or condition including, butare not limited to: diabetic nephropathy, hypertensive nephropathy,HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgAnephropathy, focal segmental glomerulosclerosis, membranousglomerulonephritis, minimal change disease, polycystic kidney diseaseand tubular interstitial nephritis.

Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,may be used to treat acute kidney injury or disease or conditionincluding, but are not limited to: ischemia-reperfusion induced, cardiacand major surgery induced, percutaneous coronary intervention induced,radio-contrast agent induced, sepsis induced, pneumonia induced, anddrug toxicity induced.

Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,may be used to treat obesity, dyslipidemia, hypercholesterolemia,Alzheimer's disease, metabolic syndrome, hepatic steatosis, type IIdiabetes, insulin resistance, diabetic retinopathy or diabeticneuropathy.

Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,may be used to prevent conception by inhibiting spermatogenesis in asubject comprising administering a therapeutically effective amount of acrystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,to a subject in need thereof.

Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,can be co-administered to a subject. The term “co-administered” meansthe administration of two or more different pharmaceutical agents ortreatments (e.g., radiation treatment) that are administered to asubject by combination in the same pharmaceutical composition orseparate pharmaceutical compositions. Thus co-administration involvesadministration at the same time of a single pharmaceutical compositioncomprising two or more therapeutic agents or administration of two ormore different compositions to the same subject at the same or differenttimes.

Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidecan be co-administered with a therapeutically effective amount of one ormore agents to treat a cancer, where examples of the agents include,such as radiation, alkylating agents, angiogenesis inhibitors,antibodies, antimetabolites, antimitotics, antiproliferatives,antivirals, aurora kinase inhibitors, apoptosis promoters (for example,Bcl-xL, Bcl-w and Bfl-1) inhibitors, activators of death receptorpathway, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager)antibodies, antibody drug conjugates, biologic response modifiers,cyclin-dependent kinase inhibitors, cell cycle inhibitors,cyclooxygenase-2 inhibitors, DVDs (dual variable domain antibodies),leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growthfactor inhibitors, heat shock protein (HSP)-90 inhibitors, histonedeacetylase (HDAC) inhibitors, hormonal therapies, immunologicals,inhibitors of inhibitors of apoptosis proteins (IAPB), intercalatingantibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors,mammalian target of rapamycin inhibitors, microRNA's, mitogen-activatedextracellular signal-regulated kinase inhibitors, multivalent bindingproteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP(adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinumchemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide-3kinase (bromodomain) inhibitors, proteosome inhibitors, purine analogs,pyrimidine analogs, receptor tyrosine kinase inhibitors,etinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids(siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, and thelike, and in combination with one or more of these agents.

BiTE antibodies are bi-specific antibodies that direct T-cells to attackcancer cells by simultaneously binding the two cells. The T-cell thenattacks the target cancer cell. Examples of BiTE antibodies includeadecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and thelike. Without being limited by theory, one of the mechanisms by whichT-cells elicit apoptosis of the target cancer cell is by exocytosis ofcytolytic granule components, which include perforin and granzyme B. Inthis regard, Bcl-2 has been shown to attenuate the induction ofapoptosis by both perforin and granzyme B. These data suggest thatinhibition of Bcl-2 could enhance the cytotoxic effects elicited byT-cells when targeted to cancer cells (V. R. Sutton, D. L. Vaux and J.A. Trapani, J. of Immunology 1997, 158 (12), 5783).

SiRNAs are molecules having endogenous RNA bases or chemically modifiednucleotides. The modifications do not abolish cellular activity, butrather impart increased stability and/or increased cellular potency.Examples of chemical modifications include phosphorothioate groups,2′-deoxynucleotide, 2′-OCH₃-containing ribonucleotides,2′-F-ribonucleotides, 2′-methoxyethyl ribonucleotides, combinationsthereof and the like. The siRNA can have varying lengths (e.g., 10-200bps) and structures (e.g., hairpins, single/double strands, bulges,nicks/gaps, mismatches) and are processed in cells to provide activegene silencing. A double-stranded siRNA (dsRNA) can have the same numberof nucleotides on each strand (blunt ends) or asymmetric ends(overhangs). The overhang of 1-2 nucleotides can be present on the senseand/or the antisense strand, as well as present on the 5′- and/or the3′-ends of a given strand.

Multivalent binding proteins are binding proteins comprising two or moreantigen binding sites. Multivalent binding proteins are engineered tohave the three or more antigen binding sites and are generally notnaturally occurring antibodies. The term “multispecific binding protein”means a binding protein capable of binding two or more related orunrelated targets. Dual variable domain (DVD) binding proteins aretetravalent or multivalent binding proteins binding proteins comprisingtwo or more antigen binding sites. Such DVDs may be monospecific (i.e.,capable of binding one antigen) or multispecific (i.e., capable ofbinding two or more antigens). DVD binding proteins comprising two heavychain DVD polypeptides and two light chain DVD polypeptides are referredto as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVDpolypeptide, a light chain DVD polypeptide, and two antigen bindingsites. Each binding site comprises a heavy chain variable domain and alight chain variable domain with a total of 6 CDRs involved in antigenbinding per antigen binding site. Multispecific DVDs include DVD bindingproteins that bind DLL4 and VEGF, or C-met and EFGR or ErbB3 and EGFR.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU),chlorambucil, CLORETAZINE® (laromustine, VNP 40101M), cyclophosphamide,decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide,KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol,mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine,temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan, rofosfamideand the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosinekinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR)inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrixmetalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9(MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR)inhibitors, thrombospondin analogs, vascular endothelial growth factorreceptor tyrosine kinase (VEGFR) inhibitors and the like.

Antimetabolites include ALIMTA® (pemetrexed disodium, LY231514, MTA),5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine),clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside,decitabine, deferoxamine, doxifluridine, eflornithine, EICAR(5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide), enocitabine,ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination withleucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan),mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolicacid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,tegafur, TS-1, vidarabine, UFT and the like.

Antivirals include ritonavir, hydroxychloroquine and the like.

Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680,Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitorsand pan-Aurora kinase inhibitors and the like.

Bcl-2 protein inhibitors include AT-101 ((−)gossypol), GENASENSE® (G3139or oblimersen (Bcl-2-targeting antisense oligonucleotide)), IPI-194,IPI-565,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(41R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)(ABT-737),N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide(ABT-263), GX-070 (obatoclax), ABT-199, and the like.

Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC®(imatinib) and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584,flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib(CYC-202, R-roscovitine), ZK-304709 and the like.

COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA®(valdecoxib), BMS347070, CELEBREX® (celecoxib), COX-189 (lumiracoxib),CT-3, DERAMAXX® (deracoxib), JTE-522,4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663(etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016,S-2474, T-614, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include EGFR antibodies, ABX-EGF, anti-EGFRimmunoliposomes, EGF-vaccine, EMD-7200, ERBITUX® (cetuximab), HR3, IgAantibodies, IRESSA (gefitinib), TARCEVA (erlotinib or OSI-774), TP-38,EGFR fusion protein, TYKERB® (lapatinib) and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4,petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166,dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecificantibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mABAR-209, mAB 2B-1 and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275,trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid andthe like.

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010,CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB® (humanrecombinant antibody to HSP-90), NCS-683664, PU24FC1, PU-3, radicicol,SNX-2112, STA-9090 VER49009 and the like.

Inhibitors of inhibitors of apoptosis proteins include HGS1029,GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.

Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE,anti-CD22-MCC-DM1, CR-0,1-vcMMAE, PSMA-ADC, MEDI-547, SGN-19 Am SGN-35,SGN-75 and the like

Activators of death receptor pathway include TRAIL, antibodies or otheragents that target TRAIL or death receptors (e.g., DR4 and DR5) such asApomab, conatumumab, ETR2-ST01, GDC0145, (lexatumumab), HGS-1029,LBY-135, PRO-1762 and trastuzumab.

Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520;CENPE inhibitors such as GSK923295A and the like.

JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and INCB018424 andthe like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 andthe like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001,rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors,including PI-103, PP242, PP30, Torin 1 and the like.

Non-steroidal anti-inflammatory drugs include AMIGESIC (salsalate),DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen),RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE®(naproxen) and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN®(indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE®(etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.

PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin)eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin),satraplatin, picoplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin,LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866,GDC-0941, BGT226, BEZ235, XL765 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and thelike.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788,ANGIOZYME™ (a ribozyme that inhibits angiogenesis (RibozymePharmaceuticals (Boulder, Colo.) and Chiron, (Emeryville, Calif.)),axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib),NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib(PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap, ZACTIMA™(vandetanib, ZD-6474), GA101, ofatumumab, ABT-806 (mAb-806), ErbB3specific antibodies, BSG2 specific antibodies, DLL4 specific antibodiesand C-met specific antibodies, and the like.

Antibiotics include intercalating antibiotics aclarubicin, actinomycinD, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin),daunorubicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitrucin,epirbucin, glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin,neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer,streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin,amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine),diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin),etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane,SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies,chTNT-1/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab),IGF1R-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX®(WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab, CD20antibodies types I and II and the like.

Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN®(exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE®(cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane),dexamethasone, DROGENIL® (flutamide), EVISTA® (raloxifene), AFEMA™(fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®(letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol),RENAGEL® (sevelamer carbonate), lasofoxifene, leuprolide acetate,MEGACE® (megesterol), MIFEPREX® (mifepristone), NILANDRON™ (nilutamide),NOLVADEX® (tamoxifen citrate), PLENAXIS™ (abarelix), prednisone,PROPECIA® (finasteride), rilostane, SUPREFACT® (buserelin), TRELSTAR®(luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelinimplant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin,goserelin) and the like.

Deltoids and retinoids include seocalcitol (EB1089, CB1093),lexacalcitrol (KH1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN®(liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436,AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.

Plant alkaloids include, but are not limited to, vincristine,vinblastine, vindesine, vinorelbine and the like.

Proteasome inhibitors include VELCADE (bortezomib), MG132, NPI-0052,PR-171 and the like.

Examples of immunologicals include interferons and otherimmune-enhancing agents. Interferons include interferon alpha,interferon alpha-2a, interferon alpha-2b, interferon beta, interferongamma-1a, ACTIMMUNE® (interferon gamma-1b) or interferon gamma-n1,combinations thereof and the like. Other agents includeALFAFERONE,(IFN-α), BAM-002 (oxidized glutathione), BEROMUN®(tasonermin), BEXXAR® (tositumomab), CAMPATH® (alemtuzumab), CTLA4(cytotoxic lymphocyte antigen 4), decarbazine, denileukin, epratuzumab,GRANOCYTE® (lenograstim), lentinan, leukocyte alpha interferon,imiquimod, MDX-010 (anti-CTLA-4), melanoma vaccine, mitumomab,molgramostim, MYLOTARG™ (gemtuzumab ozogamicin), NEUPOGEN® (filgrastim),OncoVAC-CL, OVAREX® (oregovomab), pemtumomab (Y-muHMFG1), PROVENGE®(sipuleucel-T), sargaramostim, sizofilan, teceleukin, THERACYS®(Bacillus Calmette-Guerin), ubenimex, VIRULIZIN® (immunotherapeutic,Lorus Pharmaceuticals), Z-100 (Specific Substance of Maruyama (SSM)),WF-10 (Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZADAXIN®(thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (⁹⁰Y-Ibritumomabtiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth ordifferentiation of tissue cells to direct them to have anti-tumoractivity and include krestin, lentinan, sizofiran, picibanil PF-3512676(CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosinearabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU(5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX®(ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.

Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL®(mercaptopurine).

Antimitotic agents include batabulin, epothilone D (KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE (docetaxel), PNU100940(109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO(synthetic epothilone) and the like.

Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins,NEDD8 inhibitors such as MLN4924 and the like.

Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidecan also be used as radiosensitizers that enhance the efficacy ofradiotherapy. Examples of radiotherapy include external beamradiotherapy, teletherapy, brachytherapy and sealed, unsealed sourceradiotherapy and the like.

Additionally, a crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,may be combined with other chemotherapeutic agents such as ABRAXANE™(ABI-007), ABT-100 (farnesyl transferase inhibitor), ADVEXIN®(Ad5CMV-p53 vaccine), ALTOCOR® or MEVACOR® (lovastatin), AMPLIGEN® (polyI:poly Cl₂U, a synthetic RNA), APTOSYN® (exisulind), AREDIA® (pamidronicacid), arglabin, L-asparaginase, atamestane(1-methyl-3,17-dione-androsta-1,4-diene), AVAGE® (tazarotene), AVE-8062(combreastatin derivative) BEC2 (mitumomab), cachectin or cachexin(tumor necrosis factor), canvaxin (vaccine), CEAVAC® (cancer vaccine),CELEUK® (celmoleukin), CEPLENE® (histamine dihydrochloride), CERVARIX®(human papillomavirus vaccine), CHOP® (C: CYTOXAN® (cyclophosphamide);H: ADRIAMYCIN® (hydroxydoxorubicin); 0: Vincristine)(ONCOVIN®; P:prednisone), CYPAT™ (cyproterone acetate), combrestatin A4P, DAB(389)EGF(catalytic and translocation domains of diphtheria toxin fused via aHis-Ala linker to human epidermal growth factor) or TransMID-107R™(diphtheria toxins), dacarbazine, dactinomycin,5,6-dimethylxanthenone-4-acetic acid (DMXAA), eniluracil, EVIZON™(squalamine lactate), DIMERICINE® (T4N5 liposome lotion),discodermolide, DX-8951f (exatecan mesylate), enzastaurin, EP0906(epithilone B), GARDASIL® (quadrivalent human papillomavirus (Types 6,11, 16, 18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®, GMK(ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine),halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGN-101,IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonasexotoxin, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide),lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine(hexadecylphosphocholine), NEOVASTAT®(AE-941), NEUTREXIN® (trimetrexateglucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme),ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine),ORATHECINT™ (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb(murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponinsfrom ginseng comprising 20(S)protopanaxadiol (aPPD) and20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigationalcancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol,procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID®(lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide),SORIATANE® (acitretin), staurosporine (Streptomyces staurospores),talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN®(DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR®(temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), thymitaq(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazolinedihydrochloride), TNFERADE™ (adenovector: DNA carrier containing thegene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan),tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandineplant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® (motexafingadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex),YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA®(zolendronic acid), zorubicin and the like.

Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,can also be co-administered with a therapeutically effective amount ofone or more therapeutic agents to treat an inflammatory disease orcondition, or autoimmune disease, where examples of the agents include,such as methotrexate, tofacitinib, 6-mercaptopurine, azathioprinesulphasalazine, mesalazine, olsalazine chloroquinine/hydroxychloroquine,pencillamine, aurothiomalate (intramuscular and oral), azathioprine,cochicine, corticosteroids (oral, inhaled and local injection), beta-2adrenoreceptor agonists (salbutamol, terbutaline, salmeteral), xanthines(theophylline, aminophylline), cromoglycate, nedocromil, ketotifen,ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolatemofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroidssuch as prednisolone, phosphodiesterase inhibitors, adensosine agonists,antithrombotic agents, complement inhibitors, adrenergic agents, agentswhich interfere with signalling by proinflammatory cytokines such asTNFα or IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1βconverting enzyme inhibitors, T-cell signalling inhibitors such askinase inhibitors, metalloproteinase inhibitors, sulfasalazine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNFreceptors and the derivatives p75TNFRIgG (etanercept) and p55TNFRIgG(Lenercept), sIL-1R1, sIL-1R11, sIL-6R), antiinflammatory cytokines(e.g. IL-4, IL-10, IL-11, IL-13 and TGFβ), celecoxib, folic acid,hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab,adalimumab, certolizumab, tocilizumab, abatacept, naproxen, valdecoxib,sulfasalazine, methylprednisolone, meloxicam, methylprednisoloneacetate, gold sodium thiomalate, aspirin, triamcinolone acetonide,propoxyphene napsylate/apap, folate, nabumetone, diclofenac, piroxicam,etodolac, diclofenac sodium, oxaprozin, oxycodone HCl, hydrocodonebitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra,tramadol HCl, salsalate, sulindac, cyanocobalamin/fa/pyridoxine,acetaminophen, alendronate sodium, prednisolone, cortisone,betamethasone, morphine sulfate, lidocaine hydrochloride, indomethacin,glucosamine sulf/chondroitin, amitriptyline HCl, sulfadiazine, oxycodoneHCl/acetaminophen, olopatadine HCl misoprostol, naproxen sodium,omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18BP, anti-IL-12, Anti-ILLS, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740,Roflumilast, IC-485, CDC-801, S1P1 agonists (such as FTY720), PKC familyinhibitors (such as Ruboxistaurin or AEB-071) and Mesopram. In certainembodiments, combinations include methotrexate or leflunomide and inmoderate or severe rheumatoid arthritis cases, cyclosporine and anti-TNFantibodies as noted above.

Non-limiting examples of therapeutic agents for inflammatory boweldisease with which crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidemay be co-administered include the following: budenoside; epidermalgrowth factor; corticosteroids; cyclosporin, sulfasalazine;aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole;lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide;antioxidants; thromboxane inhibitors; IL-1 receptor antagonists;anti-IL-1β monoclonal antibodies; anti-IL-6 monoclonal antibodies;growth factors; elastase inhibitors; pyridinyl-imidazole compounds;antibodies to or antagonists of other human cytokines or growth factors,for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16,IL-23, EMAP-II, GM-CSF, FGF, and PDGF; cell surface molecules such asCD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or theirligands; methotrexate; cyclosporine; FK506; rapamycin; mycophenolatemofetil; leflunomide; NSAIDs, for example, ibuprofen; corticosteroidssuch as prednisolone; phosphodiesterase inhibitors; adenosine agonists;antithrombotic agents; complement inhibitors; adrenergic agents; agentswhich interfere with signalling by proinflammatory cytokines such asTNFα or IL-1 (e.g. NIK, IKK, or MAP kinase inhibitors); IL-1β convertingenzyme inhibitors; TNFα converting enzyme inhibitors; T-cell signallinginhibitors such as kinase inhibitors; metalloproteinase inhibitors;sulfasalazine; azathioprine; 6-mercaptopurines; angiotensin convertingenzyme inhibitors; soluble cytokine receptors and derivatives thereof(e.g. soluble p55 or p75 TNF receptors, sIL-1R1, sIL-1R11, sIL-6R) andantiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and TGFβ).Preferred examples of therapeutic agents for Crohn's disease with whicha crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidecan be combined include the following: TNF antagonists, for example,anti-TNF antibodies, D2E7 (adalimumab), CA2 (infliximab), CDP 571,TNFR-Ig constructs, (p75TNFRIgG (etanercept) and p55TNFRIgG (LENERCEPT™)inhibitors and PDE4 inhibitors. Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidecan be combined with corticosteroids, for example, budenoside anddexamethasone; sulfasalazine, 5-aminosalicylic acid; olsalazine; andagents which interfere with synthesis or action of proinflammatorycytokines such as IL-1, for example, IL-1β converting enzyme inhibitorsand IL-1ra; T cell signaling inhibitors, for example, tyrosine kinaseinhibitors; 6-mercaptopurine; IL-11; mesalamine; prednisone;azathioprine; mercaptopurine; infliximab; methylprednisolone sodiumsuccinate; diphenoxylate/atrop sulfate; loperamide hydrochloride;methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water;hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide;metronidazole; thimerosal/boric acid; cholestyramine/sucrose;ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidinehydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen;promethazine hydrochloride; sodium phosphate;sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphenenapsylate; hydrocortisone; multivitamins; balsalazide disodium; codeinephosphate/apap; colesevelam HCl; cyanocobalamin; folic acid;levofloxacin; methylprednisolone; natalizumab and interferon-gamma.

Non-limiting examples of therapeutic agents for multiple sclerosis withwhich a crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,may be co-administered include the following: corticosteroids;prednisolone; methylprednisolone; azathioprine; cyclophosphamide;cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon-β1a(AVONEX®; Biogen); interferon-(31b (BETASERON®; Chiron/Berlex);interferon α-n3) (Interferon Sciences/Fujimoto), interferon-α (AlfaWassermann/J&J), interferon β1A-1F (Serono/Inhale Therapeutics),Peginterferon α 2b (Enzon/Schering-Plough), Copolymer 1 (Cop-1;COPAXONE®; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen;intravenous immunoglobulin; cladribine; antibodies to or antagonists ofother human cytokines or growth factors and their receptors, forexample, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15,IL-16, EMAP-II, GM-CSF, FGF, and PDGF. crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidecan be combined with antibodies to cell surface molecules such as CD2,CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80,CD86, CD90 or their ligands. Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidemay also be combined with agents such as methotrexate, cyclosporine,FK506, rapamycin, mycophenolate mofetil, leflunomide, an S1P1 agonist,NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone,phosphodiesterase inhibitors, adensosine agonists, antithromboticagents, complement inhibitors, adrenergic agents, agents which interferewith signalling by proinflammatory cytokines such as TNFα or IL-1 (e.g.,NIK, IKK, p38 or MAP kinase inhibitors), IL-1β converting enzymeinhibitors, TACE inhibitors, T-cell signaling inhibitors such as kinaseinhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNFreceptors, sIL-1R1, sIL-1R11, sIL-6R) and antiinflammatory cytokines(e.g. IL-4, IL-10, IL-13 and TGFβ).

Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidemay also be co-administered with agents, such as alemtuzumab,dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride,fampridine, glatiramer acetate, natalizumab, sinnabidol, α-immunokineNNSO₃, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778,calagualine, CPI-1189, LEM (liposome encapsulated mitoxantrone), THC.CBD(cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715,anti-IL-6 receptor antibody, neurovax, pirfenidone allotrap 1258(RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-beta2, tiplimotide,VLA-4 antagonists (for example, TR-14035, VLA4 Ultrahaler,Antegran-ELAN/Biogen), interferon gamma antagonists and IL-4 agonists.

Non-limiting examples of therapeutic agents for ankylosing spondylitiswith which a crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidecan be co-administered include the following: ibuprofen, diclofenac,misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib,rofecoxib, sulfasalazine, methotrexate, azathioprine, minocyclin,prednisone, and anti-TNF antibodies, D2E7 (HUMIRA®), CA2 (infliximab),CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBREL) and p55TNFRIgG(LENERCEPT®).

Non-limiting examples of therapeutic agents for asthma with which acrystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,may be co-administered include the following: albuterol,salmeterol/fluticasone, montelukast sodium, fluticasone propionate,budesonide, prednisone, salmeterol xinafoate, levalbuterol HCl,albuterol sulfate/ipratropium, prednisolone sodium phosphate,triamcinolone acetonide, beclomethasone dipropionate, ipratropiumbromide, azithromycin, pirbuterol acetate, prednisolone, theophyllineanhydrous, methylprednisolone sodium succinate, clarithromycin,zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillintrihydrate, flunisolide, allergy injection, cromolyn sodium,fexofenadine hydrochloride, flunisolide/menthol,amoxicillin/clavulanate, levofloxacin, inhaler assist device,guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl,doxycycline hyclate, guaifenesin/d-methorphan,p-ephedrine/cod/chlorphenir, gatifloxacin, cetirizine hydrochloride,mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin,pe/hydrocodone/chlorphenir, cetirizine HCl/pseudoephed,phenylephrine/cod/promethazine, codeine/promethazine, cefprozil,dexamethasone, guaifenesin/pseudoephedrine,chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate,epinephrine, methylprednisolone, anti-IL-13 antibody, and metaproterenolsulfate.

Non-limiting examples of therapeutic agents for COPD with which acrystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,may be co-administered include the following: albuterolsulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone,albuterol, salmeterol xinafoate, fluticasone propionate, prednisone,theophylline anhydrous, methylprednisolone sodium succinate, montelukastsodium, budesonide, formoterol fumarate, triamcinolone acetonide,levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate,levalbuterol HCl, flunisolide, ceftriaxone sodium, amoxicillintrihydrate, gatifloxacin, zafirlukast, amoxicillin/clavulanate,flunisolide/menthol, chlorpheniramine/hydrocodone, metaproterenolsulfate, methylprednisolone, mometasone furoate,p-ephedrine/cod/chlorphenir, pirbuterol acetate, p-ephedrine/loratadine,terbutaline sulfate, tiotropium bromide, (R,R)-formoterol, TgAAT,cilomilast and roflumilast.

Non-limiting examples of therapeutic agents for psoriasis with which acrystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidemay be co-administered include the following: calcipotriene, clobetasolpropionate, triamcinolone acetonide, halobetasol propionate, tazarotene,methotrexate, fluocinonide, betamethasone diprop augmented, fluocinoloneacetonide, acitretin, tar shampoo, betamethasone valerate, mometasonefuroate, ketoconazole, pramoxine/fluocinolone, hydrocortisone valerate,flurandrenolide, urea, betamethasone, clobetasol propionate/emoll,fluticasone propionate, azithromycin, hydrocortisone, moisturizingformula, folic acid, desonide, pimecrolimus, coal tar, diflorasonediacetate, etanercept folate, lactic acid, methoxsalen, hc/bismuthsubgal/znox/resor, methylprednisolone acetate, prednisone, sunscreen,halcinonide, salicylic acid, anthralin, clocortolone pivalate, coalextract, coal tar/salicylic acid, coal tar/salicylic acid/sulfur,desoximetasone, diazepam, emollient, fluocinonide/emollient, mineraloil/castor oil/na lact, mineral oil/peanut oil, petroleum/isopropylmyristate, psoralen, salicylic acid, soap/tribromsalan, thimerosal/boricacid, celecoxib, infliximab, cyclosporine, alefacept, efalizumab,tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874 andustekinamab.

Non-limiting examples of therapeutic agents for psoriatic arthritis withwhich a crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidemay be co-administered include the following: methotrexate, etanercept,rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide,methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate,prednisone, sulindac, betamethasone diprop augmented, infliximab,methotrexate, folate, triamcinolone acetonide, diclofenac,dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam,methylprednisolone, nabumetone, tolmetin sodium, calcipotriene,cyclosporine, diclofenac sodium/misoprostol, fluocinonide, glucosaminesulfate, gold sodium thiomalate, hydrocodone bitartrate/apap, ibuprofen,risedronate sodium, sulfadiazine, thioguanine, valdecoxib, alefacept,D2E7 (adalimumab), and efalizumab.

Examples of therapeutic agents for SLE (Lupus) with which a crystallineform II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidemay be co-administered include the following: NSAIDS, for example,diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; COX2inhibitors, for example, celecoxib, rofecoxib, valdecoxib;anti-malarials, for example, hydroxychloroquine; steroids, for example,prednisone, prednisolone, budenoside, dexamethasone; cytotoxics, forexample, azathioprine, cyclophosphamide, mycophenolate mofetil,methotrexate; inhibitors of PDE4 or purine synthesis inhibitor, forexample Cellcept®. Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidemay also be combined with agents such as sulfasalazine, 5-aminosalicylicacid, olsalazine, Imuran® and agents which interfere with synthesis,production or action of proinflammatory cytokines such as IL-1, forexample, caspase inhibitors like IL-1β converting enzyme inhibitors andIL-1ra. Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidemay also be used with T cell signaling inhibitors, for example, tyrosinekinase inhibitors; or molecules that target T cell activation molecules,for example, CTLA-4-IgG or anti-B7 family antibodies, anti-PD-1 familyantibodies. Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidecan be combined with IL-11 or anti-cytokine antibodies, for example,fonotolizumab (anti-IFNg antibody), or anti-receptor receptorantibodies, for example, anti-IL-6 receptor antibody and antibodies toB-cell surface molecules. Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidemay also be used with LJP 394 (abetimus), agents that deplete orinactivate B-cells, for example, Rituximab (anti-CD20 antibody),lymphostat-B (anti-B1yS antibody), TNF antagonists, for example,anti-TNF antibodies, D2E7 (adalimumab), CA2 (infliximab), CDP 571,TNFR-Ig constructs, (p75TNFRIgG (etanercept) and p55TNFRIgG(LENERCEPT™).

Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidecan also be co-administered with a therapeutically effective amount ofone or more agents used in the prevention or treatment of AIDS, whereexamples of the agents include, HIV reverse transcriptase inhibitors,HIV protease inhibitors, immunomodulators, and other retroviral drugs.Examples of reverse transcriptase inhibitors include, but are notlimited to, abacavir, adefovir, didanosine, dipivoxil delavirdine,efavirenz, emtricitabine, lamivudine, nevirapine, rilpivirine,stavudine, tenofovir, zalcitabine, and zidovudine. Examples of proteaseinhibitors include, but are not limited to, amprenavir, atazanavir,darunavir, indinavir, fosamprenavir, lopinavir, nelfinavir, ritonavir,saquinavir, and tipranavir. Examples of other retroviral drugs include,but are not limited to, elvitegravir, enfuvirtide, maraviroc andraltegravir.

Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidecan be co-administered with a therapeutically effective amount of one ormore therapeutic agents to prevent or treat type II diabetes, hepaticsteatosis, insulin resistance, metabolic syndrome and related disorders,where examples of the agents include, but are not limited to, insulinand insulins that have been modified to improve the duration of actionin the body; agents that stimulate insulin secretion such asacetohexamide, chlorpropamide, glyburide, glimepiride, glipizide,glicazide, glycopyramide, gliquidone, rapaglinide, nataglinide,tolazamide and tolbutamide; agents that are glucagon-like peptideagonists such as exanatide, liraglutide and taspoglutide; agents thatinhibit dipeptidyl-peptidase IV such as vildagliptin, sitagliptin,saxagliptin, linagliptin, allogliptin and septagliptin; agents that bindto the peroxisome proliferator-activated receptor gamma such asrosiglitazone and pioglitazone; agents that decrease insulin resistancesuch as metformin; agents that reduce glucose absorbance in the smallintestine such as acarbose, miglitol and voglibose.

Crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamidecan be co-administered with a therapeutically effective amount of one ormore therapeutic agents to prevent or treat acute kidney disorders andchronic kidney diseases, where examples of the agents include, but arenot limited to, dopamine, diuretics such as furosemide, bumetanide,thiazide and the like, mannitol, calcium gluconate, sodium bicarbonate,albuterol, paricalcitol, doxercalciferol, cinacalcet and bardoxalonemethyl.

The terms “treat”, “treating”, and “treatment” refer to a method ofalleviating or abrogating a disease and/or its attendant symptoms.

The terms “prevent”, “preventing”, and “prevention” refer to a method ofpreventing the onset of a disease and/or its attendant symptoms orbarring a subject from acquiring a disease. As used herein, “prevent”,“preventing” and “prevention” also include delaying the onset of adisease and/or its attendant symptoms and reducing a subject's risk ofacquiring a disease.

The phrase “therapeutically effective amount” means an amount of acompound, or a pharmaceutically acceptable salt thereof, sufficient toprevent the development of or to alleviate to some extent one or more ofthe symptoms of the condition or disorder being treated whenadministered alone or in conjunction with another pharmaceutical agentor treatment in a particular subject or subject population. For examplein a human or other mammal, a therapeutically effective amount can bedetermined experimentally in a laboratory or clinical setting, or may bethe amount required by the guidelines of the United States Food and DrugAdministration, or equivalent foreign agency, for the particular diseaseand subject being treated.

The term “subject” is defined herein to refer to animals such asmammals, including, but not limited to, primates (e.g., humans), cows,sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. Inpreferred embodiments, the subject is a human.

The following Examples may be used for illustrative purposes and shouldnot be deemed to narrow the scope of the invention.

EXAMPLES

Powder X-ray Diffraction (PXRD)

PXRD data were collected using a G3000 diffractometer (Inel Corp.,Artenay, France) equipped with a curved position sensitive detector andparallel beam optics. The diffractometer was operated with a copperanode tube (1.5 kW fine focus) at 40 kV and 30 mA. An incident beamgermanium monochrometer provided monochromatic radiation. Thediffractometer was calibrated using the attenuated direct beam atone-degree intervals. Calibration was checked using a silicon powderline position reference standard (NIST 640c). The instrument wascomputer controlled using the Symphonix software (Inel Corp., Artenay,France) and the data was analyzed using the Jade software (version 9,Materials Data, Inc., Livermore, Calif.). The sample was loaded onto analuminum sample holder and leveled with a glass slide. The sample wasirradiated with copper Kα₁ X-rays with the X-ray tube operated at 40 kVand 30 mA.

The PXRD patterns are shown in FIGS. 1 and 4. The Tables below includethe analysis and are provided with the following approximate data: 2θpositions and relative intensity using peak height to measure height %(H %) in counts per second.

Differential Scanning calorimetry (DSC)

A DSC (Q-2000, TA Instruments, New Castle, Del.) equipped with UniversalAnalysis 2000 software (Version 4.5A, TA Instruments, New Castle, Del.)was used to determine the DSC thermal traces. The temperature axis wascalibrated with biphenyl, indium, and tin standards. The cell constantwas calibrated with indium. Unless otherwise stated, the sample (2-5 mg)was encapsulated in a ventilated aluminum pan, and heated at a rate of10° C./min under a nitrogen gas flow of 50 mL/min during the study.

Thermal Gravimetric Analysis (TGA)

TGA traces were collected on a thermal balance (Q-500, TA Instruments,New Castle, Del.) equipped with a data analyzer (Universal Analysis2000, version 4.5A, TA Instruments, New Castle, Del.). Duringexperiments, the furnace was purged with nitrogen at 60 mL/min, whilethe balance chamber was purged at 40 mL/min. Temperature of the TGAfurnace was calibrated using curie points of aluminum and nickel. Samplesize ranged from 2 to 20 mg, and a heating rate of 10° C./min was used.

Preparation ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideForm I

Step 1A

A mixture of 2-bromo-1-fluoro-4-nitrobenzene (15 g, 68 mmol),2,4-difluorophenol (7.82 mL, 82 mmol), and cesium carbonate (26.7 g, 82mmol) in dimethylsulfoxide (75 mL) was heated at 110° C. for 1 hour. Thereaction mixture was cooled to ambient temperature and water (1000 mL)and saturated aqueous sodium chloride (1000 mL) were added. The mixturewas extracted with ethyl acetate (3×200 mL). The combined organics werewashed with saturated aqueous sodium chloride, dried (anhydrousmagnesium sulfate), filtered, and concentrated under reduced pressure toprovide 2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene (22.5 g,quantitative).

Step 2A

A mixture of 2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene (22.5 g,68.2 mmol), iron powder (19.04 g, 341 mmol), and ammonium chloride (7.30g, 136 mmol) in tetrahydrofuran (117 mL), ethanol (117 mL), and water(39.0 mL) was heated under reflux at 100° C. for 2 hours. The reactionmixture was cooled to just below reflux temperature, filtered throughCelite, and the filter cake washed with warm methanol (3×50 mL). Theresulting solution was concentrated under reduced pressure and thenneutralized to a pH of 8 with saturated sodium hydrogen carbonate (150mL). The mixture was extracted with ethyl acetate (3×100 mL). Thecombined organics were washed with saturated aqueous sodium chloride,dried over anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was purified by flash chromatography (silica gel, ethylacetate/hexane gradient 0-15%) to provide3-bromo-4-(2,4-difluorophenoxy)aniline (16.8 g, 82% yield).

Step 3A

5-Bromo-2-methoxy-4-methyl-3-nitropyridine (15.0 g, 60.7 mmol) wasdissolved in dimethylformamide (300 mL), and lithium methanolate (6.07mL, 6.07 mmol, 1 M) was added. The reaction mixture was heated to 100°C. To this mixture was added 1,1-dimethoxy-N,N-dimethylmethanamine (64.5mL, 486 mmol) over 10 minutes. The reaction mixture was stirred at 95°C. for 16 hours. The reaction mixture was cooled to room temperature andwater was added carefully (300 mL, exothermic). The resultingprecipitate was collected by vacuum filtration, washed with water, anddried to provide(E)-2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine(13.9 g, 45.9 mmol, 76% yield).

Step 4A

(E)-2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine(13.9 g, 45.8 mmol) and ethyl acetate (150 mL) were added to Ra-Ni 2800(pre-washed with ethanol), water slurry (6.9 g, 118 mmol) in a stainlesssteel pressure bottle and stirred for 30 minutes at 30 psi of hydrogenand room temperature. The reaction mixture was filtered, andconcentrated. The residue was triturated with dichloromethane, and thesolid collected by filtration to provide4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (5.82 g). The mother liquorwas evaporated and the residue triturated again with dichloromethane andfiltered to provide an additional 1.63 g of4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine. Total yield=7.45 g, 72%yield.

Step 5A

A solution of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (7.42 g, 32.7mmol) in dimethylformamide (235 mL) was stirred at room temperature. Tothis solution was added sodium hydride (1.18 g, 1.96 g of 60% dispersionin oil, 49.0 mmol), and the reaction mixture was stirred for 10 minutes.P-toluenesulfonyl chloride (9.35 g, 49.0 mmol) was then addedportion-wise, and the mixture was stirred at room temperature undernitrogen for 16 hours. The reaction mixture was quenched carefully withwater and the resulting beige solid collected by vacuum filtration on aBuchner funnel, and washed with water. The solid was collected and driedin a vacuum oven at 50° C. to provide 12.4 g (100%) of4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine.

Step 6A

A solution of 4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine (12.4g, 32.6 mmol) in dioxane (140 mL) was stirred at room temperature. Tothis solution was added 4M HCl in dioxane (140 mL). The reaction mixturewas stirred at 40° C. for 16 hours. The reaction mixture was cooled toroom temperature and concentrated. The residue was triturated withdiethyl ether, filtered, and rinsed with additional diethyl ether anddried to provide 4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one(11.23 g, 30.6 mmol, 94% yield) as a beige solid.

Step 7A

Sodium hydride (0.875 g, 36.5 mmol, 1.46 g of a 60% in oil dispersion)was added to a stirring solution of4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (11.2 g, 30.4 mmol)in dimethylformamide (217 mL) under nitrogen. After 30 minutes,iodomethane (2.27 mL, 36.5 mmol) was added and the solution was stirredat room temperature for 3 h. Upon addition of water (250 mL) aprecipitate formed. The precipitate was collected by vacuum filtration,rinsed with water (50 mL) and dried in a vacuum oven at 55° C. overnightto provide 11.2 g of4-bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (96%).

Step 8A

4-Bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (6.55 g,17.2 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(8.73 g, 34.4 mmol), potassium acetate (3.71 g, 37.8 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.393 g, 0.430 mmol) and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-PHOS, 0.819 g,1.72 mmol) were combined and sparged with argon for 1 hour withstirring. Dioxane (86 mL) was sparged with nitrogen for 1 hour,transferred via cannula under nitrogen to the solid components, and themixture was heated under argon at 80° C. for 5 hours. The reactionmixture was cooled to room temperature, partitioned between ethylacetate and water, and filtered through Celite. The ethyl acetate layerwas washed twice with brine, dried (Na₂SO₄), filtered and concentrated.The residue was purified by chromatography (silica gel, 25-80% ethylacetate in hexane). The resulting material from chromatography wastriturated with a minimal amount of hexanes (30 mL) and the particulatesolid was collected by filtration, rinsed with a minimal amount ofhexanes and dried to constant mass to afford6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one(5.4 g, 73%).

Step 9A

A mixture of 3-bromo-4-(2,4-difluorophenoxy)aniline (5.0 g, 11.67 mmol),6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one(3.85 g, 12.84 mmol),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.399 g,1.366 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.321 g, 0.350mmol), and potassium phosphate (6.19 g, 29.2 mmol) in dioxane (50 mL)and water (12.5 mL) was degassed and back-filled with nitrogen severaltimes. The reaction mixture was heated at 60° C. for 16 hours and thencooled to ambient temperature. The reaction mixture was partitionedbetween water and ethyl acetate. The aqueous layer was extracted withadditional ethyl acetate three times. The combined organic layers werewashed with brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash column chromatography(silica gel, 60% ethyl acetate/hexanes) to provide4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one(4.40 g, 72.3% yield).

Step 10A

A solution of4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one(4.35 g, 8.34 mmol) in dichloromethane (50 mL) was cooled to 0° C. Tothis solution was added ethanesulfonyl chloride (2.37 mL, 25.0 mmol).The reaction mixture was stirred at room temperature for 2 hours. Thesolvent was evaporated, and the residue was partitioned between ethylacetate and water. The aqueous layer was extracted with additional ethylacetate twice. The combined organic layers were washed with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 80% ethyl acetate/hexanes) to provideN-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-N-(ethylsulfonyl)ethanesulfonamide(5.34 g, 91% yield).

Step 11A

A mixture ofN-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-N-(ethylsulfonyl)ethanesulfonamide(5.3 g, 7.5 mmol), potassium hydroxide (8.43 g, 150 mmol), andN,N,N-trimethylhexadecan-1-aminium bromide (0.137 g, 0.375 mmol) intetrahydrofuran (60 mL) and water (30 mL) was heated at 90° C. for 16hours. Tetrahydrofuran was removed under reduced pressure, and theresidue was partitioned between water and ethyl acetate. The aqueouslayer was neutralized to pH=7 using 10% HCl. The aqueous layer was thenextracted with ethyl acetate. The combined organic layers were washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by flashchromatography (silica gel, ethyl acetate). The desired fractions werecombined and concentrated. The residue was triturated with 20 mL ofacetonitrile to provideN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideForm I (2.82 g, 82% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 1.23 (t, J=7.3Hz, 3H), 3.11 (q, J=7.3 Hz, 2H), 3.53 (s, 3H), 6.27-6.22 (m, 1H), 6.91(d, J=8.7 Hz, 1H), 7.13-6.93 (m, 2H), 7.19 (dd, J=8.8, 2.7 Hz, 1H),7.32-7.25 (m, 2H), 7.42-7.31 (m, 2H), 9.77 (s, 1H), 12.04 (bs, 1H). MS(ESI+) m/z 460.1 (M+H)⁺.

PXRD analysis of the Form I solid provided the X-ray diffraction peakslisted in Table 1. A portion of Form I solid was removed, heated to 190°C., and then cooled to room temperature. The resulting material whenanalyzed by PXRD provided the X-ray diffraction peaks listed in Table 2.The DSC thermogram for this material is depicted in FIG. 2. The meltingof Form I occurred at about 238.30° C. The TGA curve for this materialis depicted in FIG. 3.

Representative thermal characteristics of Form II are shown in FIGS. 5and 6. The melting of Form II occurred at about 241.15° C.

TABLE 1 Peak Listing of N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide Form I Peak Position(° 2θ) Relative Intensity 8.5 100.0 10.8 23.0 11.1 7.9 11.3 12.5 11.712.0 12.9 7.4 13.8 3.7 14.4 18.7 15.0 2.0 16.2 3.0 16.5 3.6 17.1 11.417.3 15.0 17.4 6.2 17.8 4.3 18.5 13.9 18.8 14.1 19.3 9.0 19.5 26.8 20.28.7 20.6 30.2 21.5 18.8 22.6 19.5 23.2 9.8 23.5 20.7 23.9 3.4 24.4 12.325.1 15.2

TABLE 2 Peak Listing of N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide Form I Peak Position(° 2θ) Relative Intensity 8.5 100.0 10.8 22.0 11.1 8.5 11.3 14.9 11.713.2 13.0 6.2 13.8 3.2 14.5 21.7 15.1 3.1 16.2 2.8 16.6 3.3 17.1 12.317.4 18.4 17.5 7.6 17.9 4.6 18.5 14.9 18.9 16.1 19.4 10.0 19.6 33.9 20.38.5 20.7 35.6 21.6 20.5 22.7 21.7 23.3 10.6 23.6 21.5 23.9 3.8 24.5 10.125.2 18.7

Preparation ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideForm II

Step 1B

3-Bromo-4-(2,4-difluorophenoxy)aniline (3.24 g, 10.80 mmol) andtriethylamine (4.37 g, 43.2 mmol) were stirred in dichloromethane (48.1mL) at ambient temperature. Ethanesulfonyl chloride (4.16 g, 32.4 mmol)was added dropwise and the solution stirred at ambient temperature for 1hour. The reaction mixture was concentrated under reduced pressure,dioxane (24 mL) and sodium hydroxide (10% w/v, 12 mL, 0.427 mmol) wereadded, and the solution was heated to 70° C. for 1 hour. The solutionwas neutralized to a pH of about 7 with saturated aqueous NH₄Cl (200mL). The aqueous phase was extracted with ethyl acetate (3×125 mL). Thecombined organics were washed with brine, dried (anhydrous MgSO₄),filtered, and then concentrated under reduced pressure. The residue waspurified by flash chromatography (silica gel, 0-50% ethylacetate/petroleum ether gradient,) to affordN-(3-bromo-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide (1.4 g, 3.57mmol, 33.1% yield).

Step 2B

A mixture of6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one(6.00 g, 14.0 mmol),N-(3-bromo-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide (5.77 g, 14.7mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane(0.205 g, 0.700 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.321g, 0.350 mmol) and potassium phosphate (2.97 g, 14.0 mmol) was combinedand sparged with argon for 30 minutes. A mixture of dioxane (60 mL) andwater (15 mL) was sparged with nitrogen for 30 minutes and transferredby syringe into the reaction vessel under argon. The reaction mixturewas stirred at 60° C. for 2 hours, cooled to ambient temperature, andpartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried (anhydrous sodium sulfate), treated with silicagel (2-4 g) for 45 minutes, filtered and concentrated to affordN-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide(8 g, 13.04 mmol, 93% yield).

Step 3B

N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide(8.0 g, 13 mmol), N,N,N-trimethylhexadecan-1-aminium bromide (0.238 g,0.652 mmol) and potassium hydroxide (11.9 g, 211 mmol) were combined intetrahydrofuran (66 mL) and water (22 mL) and the mixture heated at 100°C. for 14 hours. The reaction mixture was cooled to ambient temperatureand partitioned between ethyl acetate and water and the pH was adjustedto about 7 by careful addition of concentrated HCl. The organic layerwas separated, washed three times with saturated aqueous sodiumchloride, dried (anhydrous Na₂SO₄), filtered, and concentrated. Theresidue was suspended in dichloromethane and heated under reflux forfour hours and then cooled to room temperature. The resulting solid wasisolated by filtration and rinsed with dichloromethane and hexanes toafford a mixture ofN-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamideForm I and Form II (4.2 g, 9.14 mmol, 70.1% yield).

Step 4B

A portion of the mixture of Form I and Form II from Step 3B (7.5 g,16.32 mmol), was dissolved in a solvent mixture of boiling ethyl acetate(1500 mL) and ethanol (50 mL). Heating was discontinued and the hotsolution was treated with 3-mercaptopropyl functionalized silica gel(Aldrich, catalog number 538086, 10 g) and Darco G-60 (10 g), stirredfor 20 minutes, filtered through a 0.5 inch deep pad of Celite and thefiltrate was concentrated. The resulting solid was stirred in refluxingethanol (150 mL) for two hours, cooled to ambient temperature and thesolid was collected by filtration and dried to constant mass (6.517 g,87% recovery) to provideN-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamideForm II.

Form II solid gives X-ray diffraction peaks listed in Table 3. A portionof Form II solid generated in Step 4B above was removed, heated to 190°C., and then cooled to room temperature. The resulting solid whenanalyzed by PXRD provided the X-ray diffraction peaks listed in Table 4.The DSC thermogram for this material is depicted in FIG. 5. The meltingof Form II occurred at about 241.15° C. The TGA curve for this materialis depicted in FIG. 6.

TABLE 3 Peak Listing N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide Form II PeakPosition (° 2θ) Relative Intensity 6.2 11.7 9.0 6.7 11.0 5.4 12.2 18.412.6 16.2 13.1 48.1 14.1 12.1 15.5 5.8 16.3 13.0 16.5 16.9 16.9 23.217.8 32.7 18.0 100.0 18.3 15.3 18.9 60.1 20.4 8.7 21.0 13.5 21.6 13.521.8 29.7 22.1 24.3 22.9 8.9 23.2 6.2 24.4 11.0 24.6 16.0 25.5 19.6 26.330.1 26.9 20.2 27.2 12.1

TABLE 4 Peak Listing N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide Form II PeakPosition (° 2θ) Relative Intensity 6.2 10.1 9.0 6.9 11.0 5.1 12.3 20.312.6 19.7 13.1 50.5 14.1 13.5 15.6 5.1 16.4 17.5 16.5 20.3 16.9 24.117.8 33.2 18.1 100.0 18.3 14.2 18.9 70.0 20.4 8.3 21.1 15.8 21.6 14.921.8 36.2 22.1 25.5 22.9 10.3 23.2 6.1 24.4 13.2 24.7 17.0 25.6 26.426.3 41.9 27.0 21.9 27.3 12.4

The invention claimed is:
 1. An isolated crystalline form ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,wherein the crystalline form has a powder X-ray diffraction patterncomprising three or more 2θ peak values ±0.2 selected from the groupconsisting of: 6.2°, 9.0°, 12.3°, 12.6°, 15.6°, 22.1°, 25.6°, 26.3°,27.0°, and 27.3°.
 2. An isolated crystalline form ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,wherein the crystalline form has a powder X-ray diffraction patterncomprising the following 2θ peak values ±0.2: 6.2°, 9.0°, 11.0°, 12.3°,12.6°, 13.1°, 14.1°, 15.6°, 16.4°, 16.5°, 16.9°, 17.8°, 18.1°, 18.3°,18.9°, 20.4°, 21.1°, 21.6°, 21.8°, 22.1°, 22.9°, 23.2°, 24.4°, 24.7°,25.6°, 26.3°, 27.0°, and 27.3°.
 3. The crystalline form of claim 1having a powder X-ray diffraction pattern comprising three, four, five,or six 2θ peak values ±0.2 selected from the group consisting of 6.2°,9.0°, 12.3°, 12.6, 15.6°, 22.1°, 25.6°, 26.3°, 27.0°, and 27.3°.
 4. Thecrystalline form of claim 1 having a powder X-ray diffraction patterncomprising six 2θ peak values ±0.2 selected from the group consisting of6.2°, 9.0°, 12.3°, 12.6, 15.6°, 22.1°, 25.6°, 26.3°, 27.0°, and 27.3°.5. The crystalline form of claim 1 having a powder X-ray diffractionpattern comprising five 2θ peak values ±0.2 selected from the groupconsisting of 6.2°, 9.0°, 12.3°, 12.6, 15.6°, 22.1°, 25.6°, 26.3°,27.0°, and 27.3°.
 6. The crystalline form of claim 1 having a powderX-ray diffraction pattern comprising four 2θ peak values ±0.2 selectedfrom the group consisting of 6.2°, 9.0°, 12.3°, 12.6, 15.6°, 22.1°,25.6°, 26.3°, 27.0°, and 27.3°.
 7. The crystalline form of claim 1having a powder X-ray diffraction pattern comprising three 2θ peakvalues ±0.2 selected from the group consisting of 6.2°, 9.0°, 12.3°,12.6, 15.6°, 22.1°, 25.6°, 26.3°, 27.0°, and 27.3°.
 8. The crystallineform of claim 1 having a powder X-ray diffraction pattern comprising thefollowing 2θ peak values ±0.2: 6.2°, 9.0°, 12.3°, 12.6°, and 15.6°. 9.The crystalline form of claim 1 having a powder X-ray diffractionpattern comprising the following 2θ peak values ±0.2: 22.1°, 25.6°,26.3°, 27.0°, and 27.3°.
 10. The crystalline form of claim 2 having apowder X-ray diffraction pattern comprising peak values ±0.2 at 2θpositions 6.2°, 9.0°, 12.3°, 12.6°, 13.1°, 14.1°, 16.4°, 16.5°, 16.9°,17.8°, 18.1°, 18.3°, and 18.9°.
 11. The crystalline form of claim 2having a powder X-ray diffraction pattern comprising peak values ±0.2 at2θ positions 6.2°, 9.0°, 12.3°, 12.6°, 13.1°, 14.1°, 18.1°, and 18.9°.12. The crystalline form of claim 2 having a powder X-ray diffractionpattern comprising peak values ±0.2 at 2θ positions 6.2°, 9.0°, 12.3°,12.6°, 13.1°, and 18.1°.
 13. The crystalline form of claim 2 having apowder X-ray diffraction pattern comprising peak values ±0.2 at 2θpositions 9.0°, 12.3°, 12.6°, 13.1°, and 18.1°.
 14. The crystalline formof claim 1 having a differential scanning calorimetry thermogramendotherm between 240 and 242° C.
 15. The crystalline form of claim 1having a differential scanning calorimetry thermogram endotherm atapproximately 241° C.
 16. A pharmaceutical composition comprising anisolated crystalline form ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideaccording to claim 1, and at least one pharmaceutically acceptablecarrier.
 17. A method for treating cancer in a subject comprisingadministering a therapeutically effective amount of a pharmaceuticalcomposition comprising a crystalline form ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideaccording to claim 1 and at least one pharmaceutically acceptablecarrier, to a subject in need thereof.
 18. The method of claim 17wherein the cancer is selected from the group consisting of: acousticneuroma, acute leukemia, acute lymphocytic leukemia, acute myelocyticleukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma,astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia,basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer,breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma,chordoma, choriocarcinoma, chronic leukemia, chronic lymphocyticleukemia, chronic myelocytic (granulocytic) leukemia, chronicmyelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma,glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma,hepatoma, hepatocellular cancer, hormone insensitive prostate cancer,leiomyosarcoma, leukemia, liposarcoma, lung cancer,lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia,lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies ofT-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midlinecarcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small cell lung carcinoma, solid tumors (carcinomas andsarcomas), small cell lung cancer, stomach cancer, squamous cellcarcinoma, synovioma, sweat gland carcinoma, thyroid cancer,Waldenström's macroglobulinemia, testicular tumors, uterine cancer andWilms' tumor.
 19. A method of making a pharmaceutical compositioncomprisingN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideand a pharmaceutically acceptable carrier, comprising: mixing anisolated crystalline form ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,wherein the crystalline form has a powder X-ray diffraction patterncomprising three or more 2θ peak values ±0.2 selected from the groupconsisting of: 6.2°, 9.0°, 12.3°, 12.6°, 15.6°, 22.1°, 25.6°, 26.3°,27.0°, and 27.3°, with a pharmaceutically acceptable carrier.
 20. Acomposition comprising greater than 90% (w/w) crystalline form II ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,wherein the crystalline form has a powder X-ray diffraction patterncomprising three or more 2θ peak values ±0.2 selected from the groupconsisting of: 6.2°, 9.0°, 12.3°, 12.6°, 15.6°, 22.1°, 25.6°, 26.3°,27.0°, and 27.3°.
 21. A method for treating an acute kidney disease orcondition in a subject comprising administering a therapeuticallyeffective amount of a pharmaceutical composition comprising acrystalline form ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideaccording to claim 1 and at least one pharmaceutically acceptablecarrier, to a subject in need thereof, wherein said acute kidney diseaseor condition is selected from the group consisting of:ischemia-reperfusion induced kidney disease, cardiac and major surgeryinduced kidney disease, percutaneous coronary intervention inducedkidney disease, radio-contrast agent induced kidney disease, sepsisinduced kidney disease, pneumonia induced kidney disease, and drugtoxicity induced kidney disease.
 22. A method for treating a chronickidney disease or condition in a subject comprising administering atherapeutically effective amount of a pharmaceutical compositioncomprising a crystalline form ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideaccording to claim 1 and at least one pharmaceutically acceptablecarrier, to a subject in need thereof, wherein said chronic kidneydisease or condition is selected from the group consisting of: diabeticnephropathy, hypertensive nephropathy, HIV-associated nephropathy,glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmentalglomerulosclerosis, membranous glomerulonephritis, minimal changedisease, polycystic kidney disease and tubular interstitial nephritis.23. A method for treating a disease or condition in a subject comprisingadministering a therapeutically effective amount of a pharmaceuticalcomposition comprising a crystalline form ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideaccording to claim 1 and at least one pharmaceutically acceptablecarrier, to a subject in need thereof, wherein said disease or conditionis selected from the group consisting of Addison's disease, acute gout,ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease,bullous skin diseases, cardiac myopathy, cardiac hypertrophy, chronicobstructive pulmonary disease (COPD), Crohn's disease, dermatitis,eczema, giant cell arteritis, glomerulonephritis, heart failure,hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease,lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis,organ transplant rejection, osteoarthritis, pancreatitis, pericarditis,Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis,psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosingcholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis,toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis,vitiligo, vasculitis, and Wegener's granulomatosis.
 24. A method fortreating an acquired immunodeficiency syndrome (AIDS) in a subjectcomprising administering a therapeutically effective amount of apharmaceutical composition comprising a crystalline form ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideaccording to claim 1 and at least one pharmaceutically acceptablecarrier, to a subject in need thereof.
 25. A method for treating adisease or condition in a subject comprising administering atherapeutically effective amount of a pharmaceutical compositioncomprising a crystalline form ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideaccording to claim 1 and at least one pharmaceutically acceptablecarrier, to a subject in need thereof, wherein said disease or conditionis selected from the group consisting of: obesity, dyslipidemia,hypercholesterolemia, Alzheimer's disease, metabolic syndrome, hepaticsteatosis, type II diabetes, insulin resistance, diabetic retinopathyand diabetic neuropathy.
 26. A method of contraception in a male subjectcomprising administering a therapeutically effective amount of apharmaceutical composition comprising a crystalline form ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideaccording to claim 1 and at least one pharmaceutically acceptablecarrier, to a subject in need thereof.